Project Summary The parent grant, entitled ?Low-level Arsenic Exposure and Cardiovascular Disease in Multi-Ethnic Adults (MESA As)?, aims to investigate the cardiovascular effects of low-level arsenic (As) exposure in US adults of multiple racial/ethnic groups. Given the tremendous wealth and quality of information already available in MESA, the addition of high-quality As measures currently being assessed in the parent grant, and the growing need to study relevant health effects at low-levels of As exposure, we propose to expand the scope of the parent grant to assess the extent to which low-level As exposure is associated with chronic lung disease. Chronic lower respiratory disease is the fourth leading cause of death in the US. Between 1980 and 2014, the mortality rate due to chronic lung disease increased by 29.7% nationally, from 40.8 to 52.9 deaths per 100,000, respectively. Arsenic is known to induce chronic lower respiratory disease in occupational settings and highly contaminated environments. Little is known, however, on the role low-level arsenic exposure plays in chronic lower respiratory disease development in general populations. In this research supplement to support Dr. Tiffany Sanchez in developing an independent research career, we propose evaluating the extent to which low-level arsenic exposure plays a role in respiratory disease. This project will be conducted in MESA-Lung, a nested MESA sub- study which includes 3,965 MESA participants in the parent grant (~58%). MESA-Lung has extensive pulmonary markers, including longitudinal measures of lung function and lung imaging scans, and biomarkers of inflammation/repair. Thus, this MESA sub-cohort serves as an ideal study population for our proposed research. With the completion of urine metals measured in the parent grant, all data needed for this proposed project have been previously obtained. In Aim 1 we will assess the prospective association of baseline urine As with clinical chronic lower respiratory disease events and the cross-sectional and prospective association with subclinical outcomes (Spirometry measures of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and FEV1/FVC, and high-resolution computed tomography-based measures of percent emphysema and high attenuation areas). In Aim 2 we will evaluate effect modification and potential mediators of the associations in Aim 1. Priority modifiers will include tobacco smoke (smoking status and secondhand smoke), As metabolism, and one-carbon metabolism status. In addition, in an exploratory manner, we will evaluate effect modification of As on chronic lower respiratory disease by sex, race/ethnicity, and other co-exposures (air pollution, metals). Potential mediators will include markers of oxidative stress and inflammation, markers of immune function, and DNA methylation. In an exploratory manner in Aim 3 we will also evaluate the associations of metals and metal mixtures with clinical chronic lower respiratory disease incidence. This research project will deepen the understanding of low-level As exposure and the cardiopulmonary system.